Abstract:Immunotherapies have significantly improved cancer patient survival, but response rates are still limited. Thus, novel formulations are needed to expand the breadth of immunotherapies. Pathogen associated molecular patterns (PAMPs) can be used to stimulate an immune response, but several pathogen recognition receptors are located within the cell, making delivery challenging. We have employed the biodegradable polymer acetalated dextran (Ace-DEX) to formulate PAMP microparticles (MPs) in order to enhance intrac… Show more
“…Besides humoral responses, the cGAMP encapsulated ES Ac-Dex also induced cellular responses against the model antigen OVA. On a B16F10 melanoma model, the cGAMP Ac-Dex showed a better anti-tumor effect compared to three other Ac-Dex particles encapsulating different adjuvants, Murabutide, imiquimod, and Poly I:C (Watkins-Schulz et al, 2019). The successful anti-cancer immunotherapy by cGAMP Ac-Dex particles was also observed on a triple negative breast cancer cell line E0771.…”
Vaccines are powerful tools that can activate the immune system for protection against various diseases. As carbohydrates can play important roles in immune recognition, they have been widely applied in vaccine development. Carbohydrate antigens have been investigated in vaccines against various pathogenic microbes and cancer. Polysaccharides such as dextran and ÎČ-glucan can serve as smart vaccine carriers for efficient antigen delivery to immune cells. Some glycolipids, such as galactosylceramide and monophosphoryl lipid A, are strong immune stimulators, which have been studied as vaccine adjuvants. In this review, we focus on the current advances in applying carbohydrates as vaccine delivery carriers and adjuvants. We will discuss the examples that involve chemical modifications of the carbohydrates for effective antigen delivery, as well as covalent antigen-carbohydrate conjugates for enhanced immune responses.
“…Besides humoral responses, the cGAMP encapsulated ES Ac-Dex also induced cellular responses against the model antigen OVA. On a B16F10 melanoma model, the cGAMP Ac-Dex showed a better anti-tumor effect compared to three other Ac-Dex particles encapsulating different adjuvants, Murabutide, imiquimod, and Poly I:C (Watkins-Schulz et al, 2019). The successful anti-cancer immunotherapy by cGAMP Ac-Dex particles was also observed on a triple negative breast cancer cell line E0771.…”
Vaccines are powerful tools that can activate the immune system for protection against various diseases. As carbohydrates can play important roles in immune recognition, they have been widely applied in vaccine development. Carbohydrate antigens have been investigated in vaccines against various pathogenic microbes and cancer. Polysaccharides such as dextran and ÎČ-glucan can serve as smart vaccine carriers for efficient antigen delivery to immune cells. Some glycolipids, such as galactosylceramide and monophosphoryl lipid A, are strong immune stimulators, which have been studied as vaccine adjuvants. In this review, we focus on the current advances in applying carbohydrates as vaccine delivery carriers and adjuvants. We will discuss the examples that involve chemical modifications of the carbohydrates for effective antigen delivery, as well as covalent antigen-carbohydrate conjugates for enhanced immune responses.
“…Among them, Ace-DEX MPs containing cGAMP are the most effective agent inhibiting tumor growth. The discovery exclusively indicates that NK cells are required for the anti-tumor effect both in TNBC and melanoma mice models [ 132 ]. Fig.…”
Section: Activated Cgas-sting Pathway and Cancer Biotherapymentioning
The activation of the cGAS-STING pathway has tremendous potential to improve anti-tumor immunity by generating type I interferons. In recent decades, we have witnessed that producing dsDNA upon various stimuli is an initiative factor, triggering the cGAS-SING pathway for a defensive host. The understanding of both intracellular cascade reaction and the changes of molecular components gains insight into type I IFNs and adaptive immunity. Based on the immunological study, the STING-cGAS pathway is coupled to cancer biotherapy. The most challenging problem is the limited therapeutic effect. Therefore, people view 5, 6-dimethylxanthenone-4-acetic acid, cyclic dinucleotides and various derivative as cGAS-STING pathway agonists. Even so, these agonists have flaws in decreasing biotherapeutic efficacy. Subsequently, we exploited agonist delivery systems (nanocarriers, microparticles and hydrogels). The article will discuss the activation of the cGAS-STING pathway and underlying mechanisms, with an introduction of cGAS-STING agonists, related clinical trials and agonist delivery systems.
“…Four routes of administration of the loaded microparticles were able to generate robust anti-tumour immune responses, demonstrated by an up to 50 times more potent Type-1 IFN response compared to clinically used immune-activating drugs such as imiquimod. These results were achieved at a dose of 0.1ug of cGAMP, amounting to a 100-fold dose reduction compared to both PEGylated cGAMP and YSK05/c-di-GMP liposomes discussed in Section 8.1 , and a 1000-fold dose reduction compared to free cGAMP [ 128 , 129 , 133 , 145 , 146 , 147 ]. Evidently, a significantly reduced amount of drug is required with this type of DDS, which is desirable for clinical translation as high doses of STING agonists have been shown to cause T cell apoptosis [ 117 , 148 , 149 ].…”
Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a âcoldâ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.
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